Role of MMPs in AngII induced abdominal aortic aneurysms

待检验的中心假设是血管紧张素II（AngII）诱导的腹主动脉瘤（AAA）的启动和成熟是由一种特异性基质金属蛋白酶（MMP）介导的，该蛋白酶通过白细胞特异性机制分泌和/或激活。为了验证这一假设，我们提出了以下目标：目标1。确定特定MMP是否负责AngII诱导的AAA。为了确定特定MMP的作用，我们将使用具有特定MMP基因工程缺陷的小鼠。基于MMP-2、MMP-9和MMP-12在肿瘤组织中的存在及其在疾病过程中的作用，我们将集中精力研究MMP-2、MMP-9和MMP-12。此外，我们将定义的时间顺序的阐述基质金属蛋白酶和它们的内源性抑制剂在不断发展和成熟的平滑肌组织。目标2.确定AngII是否诱导MMPs从白细胞释放和/或增强邻近血管细胞分泌的MMPs的活化。为了确定AngII对MMP介导的AAA形成的直接贡献，我们将进行骨髓移植研究，其中来自MMP+/+或-/-小鼠的骨髓细胞将用于重新填充MMP+/+受体小鼠。目标3.确定AngII对MMP活性的白细胞依赖性调节的机制。我们将确定AngII是否对培养细胞中特定MMPs的合成和分泌产生直接影响。此外，我们将确定AngII是否导致MMPs激活增加。目标4。确定在AAA形成后给予选择性抑制剂时MMP抑制的效果。在初步研究中，我们证明，抑制基质金属蛋白酶阻止了血管紧张素II诱导的AAA的启动。然而，在人类疾病中，超声用于检测已经形成的AAA，因此有效的药物治疗必须减少已建立的AAA的进展或逆转其病理学。可以想象，与其在疾病起始中的作用相比，MMPs在已建立的AAA中的重塑过程中发挥不同的作用。因此，初步研究将确定广泛特异性MMP抑制剂对已形成AAA成熟过程的影响。后续研究将根据特定目的1-3中获得的数据使用更具选择性的MMP抑制剂。这项研究的意义涉及AA形成和成熟的机制的描绘，重点是潜在的发展，药物治疗的疾病。

The central hypothesis to be tested is that the initiation and maturation of angiotensin II (AngII)-induced abdominal aortic aneurysms (AAAs is mediated by a specific matrix metalloproteinase (MMP) that is secreted and/or activated via a leukocyte-specific mechanism. To test this hypothesis, we propose the following aims: Aim 1. Determine whether a specific MMP is responsible for AngII- induced AAA.. To identify the action of a specific MMP, we will use mice with genetically engineered deficiencies of specific MMPs. We will focus our efforts on MMP-2, -9, and -12, based on the demonstration of their presence in aneurysmal tissue and their previous inferred roles in the disease process. Further, we will define the temporal sequence of elaboration of MMPs and their endogenous inhibitors in evolving and mature aneurysmal tissue. Aim 2. Determine whether AngII induces the release of MMPs from leukocytes and/or enhances the activation of MMPs secreted by neighboring vascular cells. To determine the direct contribution of AngII on MMP mediated AAA formation, we will perform bone marrow transplantation studies in which bone marrow cells from MMP+/+ or -/- mice will be used to repopulate MMP+/+ recipient mice. Aim 3. Determine the mechanism of AngII on leukocyte-dependent regulation of MMP activity. We will determine whether AngII exerts a direct effect on the synthesis and secretion of specific MMPs in cultured cells. Further, we will define whether AngII results in increased activation of MMPs. Aim 4. Determine the effects of MMP inhibition when selective inhibitors are administrated after the formation of AAAs. In preliminary studies we demonstrated that inhibition of MMPs prevented the initiation of AngII-induced AAA. However, in the human disease ultrasound is used to detect an already formed AAA, and thus an effective pharmacologic treatment would have to either reduce the progression or reverse the pathology of an established AAA. It is conceivable that MMPs play a different role in the remodeling process in established AAAs, as compared to their role in the initiation of the disease. Therefore, initial studies will determine the effects of broad specificity MMP inhibitors on the maturation process of an already formed AAA. Subsequent studies will use more selective inhibitors of MMPs based on data obtained in Specific Aims 1-3. The significance of this research relates to delineation of mechanism for AA formation and maturation, with emphasis on potential development of pharmacological treatments of the disease.